N,N-dimethyl imidodicarbonimidic diamide is a biguanide drug, the generic name of which is metformin. When this drug is administered to type 2 diabetic patients or glucose intolerant patients, it can exhibit blood glucose lowering action by controlling glucose formation in the liver and increasing glucose utilization in muscles and improve lipid metabolism, thus preventing the development and deterioration of diabetes complications and treating diabetes complications.
It can be seen in several papers that only metformin among oral anti-diabetic drugs is a first-choice drug. Particularly, it was proved that metformin has the effect of activating AMPK, and thus the propriety of clinical effects thereof was demonstrated. It was reported that AMPK is a key enzyme physiologically controlling metabolism of carbohydrate and lipid, and metformin is effective in normalizing high glucose level, improving the condition of lipid, normalizing amenorrhea, ovulation and pregnancy, treating fatty liver, and preventing and treating p53 gene-deficient cancers by activating said enzyme.
According to a report by the Abramson Cancer Center of the University of Pennsylvania, metformin, an AMPK activator, is effective for the prevention and treatment of p53 gene-deficient cancers [Monica Buzzai, et al. Systemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs p53 gene-Deficient Tumor Cellgrowth, Cancer Res 2007; 67:(14); Jul. 15, 2007].
The free base form of metformin is pharmaceutically useful, but has low stability. For this reason, metformin is administered in the form of a pharmaceutically acceptable acid addition salt.
Korean Patent No. 90,479 discloses that metformin prepared in the form of a pharmaceutically acceptable salt must be able to satisfy the following four physical and chemical standards: (1) good solubility; (2) good stability; (3) non-hygroscopicity; (4) processability into a tablet formulation. However, it is very difficult that the pharmaceutically acceptable acid addition salt of metformin satisfies all the four standards.
Studies on acid addition salts other than metformin hydrochloride have been conducted before. CN 1962661A discloses the preparation of metformin folate using folic acid which is used as an anti-pernicious anemia factor. International Patent Publication No. WO 2005/033067 discloses metformin 1,2,6,7,8,8a-hexahydro-beta, gamma, 6-trihydroxy-2-methyl-8-[2s]-2-methyl-1-oxobutoxy]-, (beta R, gamma R,1S,2S,6S,8S,8aS)-1-naphthaleneheptanoic acid which is used to treat hyperlipidemia and hyperglycemia. U.S. Pat. No. 3,957,853 discloses metformin acetylsalicylate, and U.S. Pat. No. 4,028,402 discloses novel acid addition salts of biguanide compounds. U.S. Pat. No. 4,080,472 discloses metformin clofibrate for treating diabetes-related diseases, and U.S. Pat. No. 6,031,004 discloses a pharmaceutical composition comprising metformin fumarate, succinate and maleate and the use thereof. In addition, U.S. Pat. No. 4,835,184 discloses p-chlorophenoxy-acetic acid salt, and U.S. Pat. No. 3,903,141 discloses adamantane acid salt.
As described above, studies on acid addition salts of metformin have been constantly conducted, but only metformin hydrochloride has been approved for use as a drug to date and has been widely used as an agent for treating non-insulin dependent diabetes mellitus. The conventional dosage of metformin hydrochloride is not more than 2550 mg/day, and a tablet comprising 500 mg or 750 mg of metformin hydrochloride is administered at mealtime twice or three times a day. However, for pharmacological effects, such metformin hydrochloride and other acid addition salts must have improved physical and chemical properties, including improved solubility, stability, non-hygroscopicity and anti-adhesive properties, and reduced toxicity.
Meanwhile, studies on various pharmacological effects of malic acid have recently been actively conducted. Malic acid is in the form of white crystal or crystalline powder and has a slightly specific odor or is odorless. It is insoluble in ether, but well soluble in water and alcohol. It is involved in the Krebs cycle, the human metabolic process, and has excellent effects against arteriosclerosis or hypertension.
Studies on malic acid itself have been actively conducted, and the significant effects of malic acid as food have been reported. However, the effects of metformin malate as disclosed in the present invention have not been reported, and the interaction of malic acid with metformin has also not been reported.
Meanwhile, in a process of producing metformin in the form of a free base according to prior patents (U.S. Pat. No. 4,080,472), there is a problem in that the use of an ion-exchange resin column, or severe production conditions, including as the reflux of solvent by heating and the filtration of hot solution, are required to remove hydrochloric acid from metformin hydrochloride.